microRNA target site RNA-directed oligonucleotide topical therapeutics in psoriasis
microRNA 靶位点 RNA 引导的寡核苷酸局部治疗银屑病
基本信息
- 批准号:10426347
- 负责人:
- 金额:$ 18.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsAminesAnti-Inflammatory AgentsAntibodiesArtificial nanoparticlesAutoimmune DiseasesAutoimmunityBindingBiological ProductsChronic small plaque psoriasisCutaneousDNADevelopmentDiseaseEstersFluorochromeFormulationGene ExpressionGenerationsGenesGenetic MaterialsGoalsHumanImiquimodImmuneImmune systemIn VitroIndividualInflammatoryInfluentialsInterleukin-17InterleukinsJordanLabelMediatingMessenger RNAMicroRNAsModelingMolecularMolecular TargetMultiple SclerosisMusNucleic AcidsOligonucleotidesPathogenicityPenetrationPlayPolymersPre-Clinical ModelProductionProteinsPsoriasisRNARoleSiteSkinSystemTherapeuticTopical applicationToxic effectTranscriptValidationXenograft Modelautoimmune uveitisbaseconfocal imagingcytokinedesigndetection assaydrug developmentgene productin vivoin vivo evaluationinnovationinterleukin-23mouse modelnanoparticlenovelnovel drug classnovel therapeuticsparticlerecruitskin xenografttherapeutic target
项目摘要
Abstract
The IL-17A/IL-23 pro-inflammatory axis has been established as an influential therapeutic target in
psoriasis. However, long-term systemic treatment with IL-17- and IL-23-directed antibody biologics can
be immunosuppressive and should be reserved for the more severe disease manifestations. This
proposal is focused on the development of topical oligonucleotides targeting IL-17A and IL-23
transcripts. Although topical treatments for plaque psoriasis exist, their efficacy is modest. A highly
specific therapy that effectively penetrates plaques for topical treatment of plaque psoriasis continues to
be a significant unmet need. Our therapeutic approach is a novel one, based on an "enhancing
microRNA" mechanism. We have begun developing an innovative platform of target site blocker (TSB)
oligonucleotides that interfere with the enhancing effect of miR466l-3p (miR466) in an individual target
mRNA-specific fashion, thereby repressing expression of only that gene. We have successfully
generated an IL-17A mRNA-specific TSB that is highly effective in IL-17-dependent murine
immune/inflammatory models of multiple sclerosis, autoimmune uveitis, and topically in imiquimod
(IMQ)- induced psoriasis. Our hypothesis that IL-17A- and IL-23- directed TSB oligos, formulated for
highly penetrable topical use, will synergistically represent a novel, highly specific, RNA-directed
treatment in psoriasis. We have assembled an outstanding collaborative team, which includes Dr. Mark
Saltzman, an expert in nucleic acid targeting through nanoparticles, and Dr. Jordan Pober, who has
developed human-to-mouse skin xenograft models. Our team now proposes to: (1) generate an IL-23-
specific TSB oligonucleotide with in vitro and in vivo (IMQ-induced psoriasis) validation, (2) optimize
poly(amine-co-ester) (PACE) nanoparticle (NP)-loaded IL-23 and IL-17A TSBs, with testing in vivo
(IMQ model), and (3) determine the penetrability of the TSB-loaded NPs into human skin, using human-
to-mouse skin xenografting and confocal imaging-based penetration analysis. This molecular,
preclinical model and biomedical nanoparticle engineering promises to develop novel therapeutic
molecules for topical targeting of the IL-17A/23 axis in plaque psoriasis.
摘要
IL-17 A/IL-23促炎轴已被确立为在炎症性疾病中有影响力的治疗靶点。
银屑病然而,用IL-17和IL-23定向的抗体生物制剂进行长期全身治疗,
免疫抑制,应保留用于更严重的疾病表现。这
一项提案的重点是开发靶向IL-17 A和IL-23的局部寡核苷酸
成绩单虽然存在斑块状银屑病的局部治疗,但其疗效不高。一个高度
有效穿透斑块用于斑块状银屑病局部治疗的特定疗法继续
这是一个重大的未满足的需求。我们的治疗方法是一种新的方法,基于“增强
microRNA”机制。我们已经开始开发一个创新的靶点阻断剂(TSB)平台
干扰miR 466 l-3 p(miR 466)在单个靶标中的增强作用的寡核苷酸
mRNA特异性方式,从而仅抑制该基因的表达。我们已经成功
产生了IL-17 A mRNA特异性TSB,其在IL-17依赖性小鼠中高度有效。
多发性硬化症、自身免疫性葡萄膜炎的免疫/炎症模型,以及咪喹莫特的局部给药
(IMQ)诱发的牛皮癣。我们的假设是,IL-17 A-和IL-23-定向TSB寡核苷酸,配制用于
高度渗透的局部使用,将协同代表一种新的,高度特异性的,RNA导向的
牛皮癣的治疗方法我们组建了一个优秀的合作团队,其中包括马克博士
Saltzman博士是通过纳米粒子进行核酸靶向的专家,Jordan Pober博士是
开发了人-小鼠皮肤异种移植模型。我们的团队现在提出:(1)产生IL-23-
特异性TSB寡核苷酸体外和体内(IMQ诱导银屑病)验证,(2)优化
聚(胺-共-酯)(PACE)纳米颗粒(NP)-负载的IL-23和IL-17 A TSB,并进行体内测试
(IMQ模型),和(3)使用人-
小鼠皮肤异种移植和基于共聚焦成像的穿透分析。这种分子,
临床前模型和生物医学纳米粒子工程有望开发新的治疗方法
用于斑块状银屑病中IL-17 A/23轴的局部靶向分子。
项目成果
期刊论文数量(0)
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{{ truncateString('JEFFREY R. BENDER', 18)}}的其他基金
IL-17A mRNA-targeted oligonucleotide therapeutics in Idiopathic Pulmonary Fibrosis (IPF)
IL-17A mRNA 靶向寡核苷酸治疗特发性肺纤维化 (IPF)
- 批准号:
10761365 - 财政年份:2023
- 资助金额:
$ 18.24万 - 项目类别:
Immune cell skewing with RNA target site oligonucleotides to promote vascular smooth muscle cell homeostasis
RNA靶位点寡核苷酸倾斜免疫细胞促进血管平滑肌细胞稳态
- 批准号:
10593490 - 财政年份:2022
- 资助金额:
$ 18.24万 - 项目类别:
microRNA target site RNA-directed oligonucleotide topical therapeutics in psoriasis
microRNA 靶位点 RNA 引导的寡核苷酸局部治疗银屑病
- 批准号:
10287633 - 财政年份:2021
- 资助金额:
$ 18.24万 - 项目类别:
Competitive macrophage microRNA-RNA binding protein interactions in wound repair
伤口修复中竞争性巨噬细胞 microRNA-RNA 结合蛋白相互作用
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9439844 - 财政年份:2017
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Competitive macrophage microRNA-RNA binding protein interactions in wound repair
伤口修复中竞争性巨噬细胞 microRNA-RNA 结合蛋白相互作用
- 批准号:
10001549 - 财政年份:2017
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Modulation neuroinflammation through interference of cooperative microRNA-RNA-binding protein interactions
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